A Systematic Review of the Impact of Fat Quantity and Fatty Acid Composition on Postprandial Vascular Function in Healthy Adults and Patients at Risk of Cardiovascular Disease

Atherosclerosis is a key risk factor for developing cardiovascular diseases (CVDs). Flow-mediated dilation (FMD), which reflects vascular reactivity, as well as pulse wave velocity (PWV) and augmentation index (AIx), both markers of arterial stiffness, have emerged as noninvasive, subclinical atherosclerotic markers for the early stages of altered vascular function. In addition to the long-term effects of diet, postprandial processes have been identified as important determinants of CVD risk, and evidence suggests an acute effect of fat quantity and fatty acid (FA) composition on vascular function. However, robust analyses of this association are lacking, especially concerning parameters of arterial stiffness. Therefore, we carried out a systematic literature search in PubMed, Scopus, and the Cochrane Library to investigate the impact of fat quantity and FA composition of meals on postprandial vascular function. Postprandial studies measuring FMD, PWV, and/or AIx in healthy adults and subjects with increased CVD risk (e.g., those with hypercholesterolemia or metabolic syndrome) were analyzed. In total, 24 articles were included; 9 studies focused on the effect of high-fat meals compared with control; and 15 studies investigated the effects of different fat sources. We found that consumption of a high-fat meal causes a reduction in FMD (decrease in vasodilation) and AIx (decrease in arterial stiffness). For eicosapentaenoic acid/docosahexaenoic acid (from fish oil), postprandial assessment (FMD and AIx) indicates a beneficial effect on vascular function. There is limited evidence of an influence of CVD risk on the vascular response to meals with varying fat doses or FA composition. However, meaningful conclusions were difficult to draw because of the large heterogeneity of the studies. Inconsistent results regarding both the impact of fat dose and FA composition on postprandial vascular function should be noted. We propose standardized methods for postprandial protocols to improve data quality in future studies. This review was registered in PROSPERO as CRD42022352986.


Introduction
In the past few decades, the number of global, cardiovascular disease (CVD)-related deaths has steadily increased, from 12.1 million in 1990 to 18.6 million in 2019 [1].According to the American Heart Association, an estimated 19.1 million people worldwide died in 2020 because of CVDs, with the highest age-standardized mortality rates in Eastern Europe and Central Asia [2].Alongside increases in mortality, CVD-attributable disability-adjusted life years, years of life lost, and years lived with disability have increased considerably [1].Atherosclerosis plays a critical role in the development of CVDs, including as an underlying cause of myocardial infarction and stroke [3].During atherogenesis, an initially reversible fatty streak forms into a fibrous fatty lesion that becomes an atheroma [4].Over time, this atherosclerotic plaque can rupture or erode, resulting in a cardiovascular event.The early stage of atherosclerosis is characterized by endothelial dysfunction [5,6].Endothelial dysfunction describes a functional impairment of the endothelium.Characteristics include a decreased vasodilatation, a proinflammatory state, and prothrombotic properties [7].Evidence also suggests an association between atherosclerosis and arterial stiffness [8,9].Arterial stiffness is influenced by age and increased blood pressure [10], and structural alterations (e.g., fragmentation of elastic lamellae, increased collagen and calcium content) play a central role in its development [11].
In developed societies, humans spend ~18 h of the day in a postprandial state [12] with continuously fluctuating diurnal lipemia [13].Evidence suggests that postprandial lipemia leads to temporary, low-grade endothelial dysfunction mediated by local oxidative stress [14][15][16][17].According to current hypotheses, this enhanced oxidative stress reduces the availability of nitric oxide (NO) by increasing breakdown and reducing production [14].NO plays an essential role in vasodilation, and reduced NO availability, resulting from either decreased production or activity, can cause endothelial dysfunction and contribute to atherosclerosis [18].Thus, postprandial hypertriglyceridemia in response to a high-fat meal (HFM) may result in endothelial dysfunction, a marker of early stage of atherosclerosis, mediated by local oxidative stress and reduced NO availability.
There is convincing evidence that a dose-response relationship exists between total fat intake and postprandial triglyceride (TG) response [19].In addition, 2 recent meta-analyses demonstrated that the fatty acid (FA) composition of a test meal influences the extent of postprandial lipemia [20,21].Considering the detrimental effect of postprandial TGs on endothelial function, impaired vascular function is likely influenced by the amount and composition of fat ingested.Previous reviews on the acute effects of single HFMs on vascular function focused mainly on flow-mediated dilation (FMD) [22,23], revealing evidence of a marked decrease in FMD in the postprandial state compared with baseline values [23] and low-fat meals (LFMs) [22].Concerning FA composition, evidence suggests an adverse effect of MUFAs [22] and a beneficial effect of long-chain n-3 (ω-3) PUFAs [24] on postprandial FMD.However, the overall evidence regarding the acute effects of FA composition on vascular function remains inconclusive [22,25].
In a recently published meta-analysis, Fewkes et al. [23] concluded that the effect size of an HFM on postprandial FMD is influenced by several factors, including age and BMI.Previously, we found that meals rich in SFAs provoke greater postprandial lipemia than meals with high amounts of unsaturated FA, especially in older subjects and/or subjects with elevated BMI [19].These results suggest that especially in adults with certain CVD risk factors (e.g., obesity), high-fat doses and, in particular, SFA-rich meals, may have detrimental effects on postprandial vascular function.
Given this background, we aimed to systematically review and critically evaluate the existing evidence on the acute effects of fat dose and FA composition on vascular function assessed by FMD, pulse wave velocity (PWV), and augmentation index (AIx).An additional aim was to investigate whether acute changes in vascular function differ between metabolically healthy individuals and participants with increased CVD risk (e.g., those with obesity, metabolic syndrome, and hypertriglyceridemia).In addition, to maximize practical relevance, we focused on mixed meals.
The FMD test was developed in 1992 by Celermajer et al. [34] and measures the endothelial-dependent vessel diameter change in response to blood flow-associated shear stress after a cuff occlusion period (recommended for 5 min) [26].There are significant correlations between FMD and invasive measures of coronary artery changes [35] and brachial FMD and future cardiovascular events [36].
Likewise, PWV is an independent predictor of CVD risk and cardiovascular events [27].PWV c-f is calculated by dividing the distance between the common carotid artery and the common femoral artery by the transit time of the pulse wave between these points [28].A higher PWV indicates a higher arterial stiffness [27].In the 2018 European Society of Cardiology/European Society of Hypertension Guidelines for the management of arterial hypertension, the cut-off value for an influence of PWV c-f on CVD risk was set at 10 m/s [37].According to the European Network for Noninvasive Investigation of Large Arteries, PWV c-f is regarded as the gold standard measurement of arterial stiffness [28].
Similar to the PWV, AIx serves as a surrogate parameter of arterial stiffness and these parameters correlate strongly [38].The AIx is determined during pulse wave analysis [29].It is a measure of wave reflection during systole and is usually adjusted to the heart rate by which it is influenced [27].AIx correlates significantly with several CVD risk scores [29].All 3 parameters of vascular function (FMD, PWV, and AIx) are reproducible [35,39].

Literature search
To identify suitable studies, the databases of PubMed (https://pubmed.ncbi.nlm.nih.gov/),Scopus (https://www.scopus.com),and the Cochrane Library (https://www.cochranelibrary.com)were searched using the search term "postprandial AND fat AND meal AND (arterial stiffness OR flow mediated dilatation OR pulse wave velocity OR pulse wave analysis)."The initial database searches were conducted between July and August 2022, and the last update was made in June 2023.Both authors independently reviewed the identified papers and compared them with the inclusion and exclusion criteria.The main inclusion criteria (Table 1) were as follows: human intervention trial; adult participants; preparation of meals with fat sources (e.g., plant oils and dairy products); periodic measurement of postprandial FMD, PWV, and/or AIx; and paper written in English.To investigate the impact of HFMs on postprandial vascular function, studies were included if !1 HFM and 1 LFM were served or if !1 HFM meal was served and participants fasted as a control.To analyze the impact of the FA composition on postprandial vascular function, studies were included if the participants consumed !2 HFMs with varying FA compositions (e.g., SFA-rich compared with PUFA-rich).Articles were excluded if a tolerance test (e.g., fat tolerance test) was performed, or if chronic effects of total fat intake or FA composition were investigated.Furthermore, pilot studies and conference papers were excluded (Table 1).Studies were selected by consensus of both the authors (Figure 1).This review was registered in PROSPERO (CRD42022352986).

Results
Using the search string, 116 articles were identified during the systematic literature search in PubMed.On the basis of these abstracts, 77 publications were excluded because they did not fulfill the inclusion criteria and/or fulfilled !1 exclusion criterion (Table 1).The remaining 39 full texts were screened, of which 23 articles were rated as suitable for this review and thus included in the analysis.Using the same search string, literature searches in the Cochrane Library and Scopus were performed, revealing 112 and 3 publications, respectively.On the basis of the titles and abstracts, 76 duplicates were removed, and an additional 38 articles were excluded according to the inclusion and exclusion criteria (in total, 114 excluded abstracts).The remaining full text was assessed and rated as suitable for this review.In total, 24 publications were included in this analysis (Figure 1), which were published between 1999 and 2021.
The effect of fat dose on FMD in healthy adults and those with CVD risk factors In 7 studies, FMD (%) was measured in metabolically healthy adults [40,[42][43][44][45][46][47] (Table 2).In 5 of these, interventions consisted of an HFM and an LFM [40,[42][43][44]47].Esser et al. [43] reported a small but significant decrease in FMD (%) from baseline 3 h after ingestion of the HFM (95 g fat) and LFM (14.5 g fat), without significant differences between the 2 meals.Bae et al. [40] and Benson et al. [42] observed a significant decrease in FMD (%) from preprandial values in response to the HFM (fat content: 53.4 g, 1 g/kg body weight [BW]), but did not detect a significant change in FMD (%) after consumption of the LFM (fat content: 3 g, 0.04 g/kg BW).In contrast, Poitras et al. [44] and Williams et al. [47] found no effect of either an HFM (fat content: 54 g, 64.4 g) or LFM (fat content: 0 g, 18.4 g) on postprandial FMD (%) (Table 2).In 2 studies [45,46], FMD (%) was measured after consumption of 1 or 2 consecutive HFMs and on a different day during a fasting period (Table 2).Tushuizen et al. [45] reported a significant decrease in FMD (%) from baseline after a fat-rich lunch that was ingested 4 h after a fat-rich breakfast (each meal: 50 g fat).The difference in FMD (%) at the equivalent time point during the fasting protocol tended toward statistical significance (P ¼ 0.051).Patik et al. [46] observed that 2 h postprandially, a fat-rich, fast-food meal (55 g fat) led to a significant decrease in FMD (%) from baseline compared with the fasting protocol; however, 2 h later, there was no significant difference in FMD (%) change from baseline between conditions.In both studies, the fasting state had no influence on FMD (%) (Table 2).
The literature search revealed one study in which the effects of an HFM (53.4 g fat) and an LFM (3 g fat) on FMD (%) were measured in participants with enhanced CVD risk (Table 3).Bae et al. [41] reported no significant effects of the test meals on postprandial FMD (%) in adults with CAD.

The effect of fat dose on AIx and PWV in healthy adults and those with CVD risk factors
Two studies investigated the impact of an HFM on AIx (%) [43,48] (Tables 2 and 4).In healthy adults, Esser et al. [43] observed a significant decrease in heart rate corrected AIx (%) from baseline after eating both an HFM (95 g fat) and an LFM (14.5 g fat), with no significant difference between groups (Table 2).Phillips et al. [48] reported that in lean adults, non diabetic adults with obesity, and individuals with T2DM, AIx (%) decreased from baseline after consumption of an HFM (57.5 g fat) but remained unchanged during the fasting period (Table 4).
No studies investigating the effects of fat dose on vascular function measured PWV (m/s).

The effect of FA composition on FMD in healthy adults and those with CVD risk factors
The literature search revealed 7 studies investigating the impact of FA composition on FMD (%) in healthy adults [49,[51][52][53][54]62,63] (Tables 5 and 7).Of these, 3 found that a HFM led to a decrease in FMD (%) from baseline, while another meal, enriched with a different vegetable fat source, had no influence on postprandial FMD (%) [49,51,62].Specifically, Berry et al. [49] reported a decrease in FMD (%) from baseline after a meal enriched with high-oleic sunflower oil (Table 5), whereas Cort es et al. [62] reported similar results after a meal enriched with olive oil (also rich in oleic acid) (Table 7).By contrast, meals enriched with a shea butter blend (refined shea butter blended with sunflower oil, rich in stearic acid) or shelled walnuts (rich in linoleic acid) had no influence on postprandial FMD (%) [49,62].Nicholls et al. [51] reported a significant decrease in FMD (%) from baseline 3 h after consumption of a SFA-rich meal (enriched with coconut oil) but not in response to a PUFA-rich meal (enriched with safflower oil) (Table 5); responses were not significantly different between meals.After 6 h, the effect of the SFA-rich meal on FMD (%) was no longer significantly different compared with the baseline.Rudolph et al. [52] observed that 3 fast-food meals administered with varying FA profiles (providing different amounts of SFAs and trans FAs) provoked significant reductions in FMD (%) from baseline without significant differences between meals (Table 5).The remaining 3 studies did not detect significant postprandial changes in FMD (%) subsequent to test meals [53,54,63] (Tables 5 and 7).Meals contained SFA-and MUFA-rich foods [53], SFA-and PUFA-rich foods [54], or butter (SFA-rich) and olive oil (MUFA-rich) as fat sources [63].
In addition to healthy adults, 2 of the above-mentioned studies also included hypercholesterolemic individuals [62] and subjects with type 1 diabetes mellitus (T1DM) [63] (Table 7).In hypercholesterolemic individuals, Cort es et al. [62] reported a decrease in FMD (%) from baseline in response to a meal enriched with olive oil (rich in oleic acid), whereas FMD (%) increased from baseline after ingestion of the meal with shelled walnuts (rich in linoleic acid).Cutruzzol a et al. [63] found that compared with a meal enriched with butter (rich in SFAs, especially lauric acid), FMD (%) was significantly higher after a meal containing extra virgin olive oil (predominantly composed of MUFAs) (Table 7).Four further studies, including adults with CVD risk factors were analyzed [58][59][60][61] (Table 6).Three did not detect significant differences in FMD (%) after ingestion of meals enriched with refined bleached deodorized palm olein or olive oil [61], a breakfast and lunch containing conventional dairy products or FA-modified dairy products (decreased SFA amount and increased MUFA amount) [58], or meals enriched with fat sources consisting mainly of SFAs (butter), MUFAs (refined olive oil and olive oil and canola oil-blended spread), or n-6 PUFAs (safflower oil and spread) [59] (Table 6).West et al. [60] included adults with T2DM and differentiated between individuals with high-and low fasting TGs.In the group with low fasting TGs, FMD (%) did not change significantly in response to test meals rich in MUFAs (fat source: high-oleic safflower oil, canola oil), MUFAs þ α-linolenic acid (ALA) (fat sources: canola oil, high-oleic safflower oil, and safflower oil), or MUFAs þ EPA/DHA (fat sources: high-oleic safflower oil, safflower oil, and sardine oil).In the group with high fasting TGs, there was no change in FMD (%) following the MUFA meal, but FMD (%) showed a significant increase from baseline 4 h after ingestion of the MUFA þ ALA and the MUFA þ EPA/DHA meal, leading to a significant treatment-group interaction (Table 6).

The effect of FA composition on AIx in healthy adults and those with CVD risk factors
The literature search revealed 3 studies that investigated the effects of FA composition on AIx (%) in healthy subjects [49,50,55] (Table 5).Berry et al. [49] reported a significant decrease in central and peripheral AIx (%) from baseline in response to test meals enriched with shea butter blend (refined shea butter blended with sunflower oil, rich in stearic acid) and high-oleic sunflower oil (Table 5); there was no significant difference between test meals.Similarly, Lithander et al. [50] observed a significant reduction in AIx (%) and AIx 75 (%, standardized to a heart rate of 75 bpm) from baseline after a SFA-rich meal (fat sources: double cream, sunflower oil; rich in palmitic acid) and a MUFA-rich meal (fat source: olive oil; rich in oleic acid) (Table 5).The effect on AIx 75 (%) remained significant after adjustment for mean arterial pressure (MAP), whereas the effect on AIx (%) was no longer significant when adjusted for increases in heart rate and MAP.There was no significantly different effect of MUFA-rich meal compared with SFA-rich meal on AIx or AIx 75 (%).Chong et al. [55] found that following a postprandial AIx 75 (%) reduction in response to both meals, the AIx 75 (%) increased to a lower extent after a meal enriched with EPA and DHA compared with a control meal (fat source: palm olein and soybean oil) (Table 5).
Two publications investigated the effects of FA composition on AIx (%) in adults with CVD risk factors [56,57] (Table 6).Kendall et al. [56] reported that in response to white bread, butter, and cheese (high SFA content), as well as to white bread and pistachios (high MUFA and PUFA content), AIx (%) decreased from baseline in subjects with metabolic syndrome (Table 6).However, the change from fasting was not significantly different between meals.McManus et al. [57] observed that compared with a meal enriched with palm and soy bean oil (control meal), the decrease in AIx (%) was significantly greater when subjects with CVD risk factors consumed a meal enriched with palm oil, soy bean oil, and DHA (palm and soybean oil mixture partly replaced by DHA-rich oil).Compared with the control meal, a meal enriched with palm oil, soy bean oil, and EPA (palm and soybean oil mixture partly replaced by EPA-rich oil) tended to cause a greater decrease in AIx (%, P ¼ 0.06) (Table 6).

The effect of FA composition on PWV in healthy adults and those with CVD risk factors
In 2 of the above-mentioned studies, PWV (m/s) was measured to analyze the effect of FA composition on arterial stiffness in healthy subjects [49,50] (Table 5).Compared with baseline values, Berry et al. [49] reported no changes in PWV c-f (m/s) measured 3 h after ingestion of meals enriched with high-oleic sunflower oil or shea butter blend (refined shea butter blended with sunflower oil, rich in stearic acid) (Table 5).Regardless of the FA composition of test meals (SFA meal rich in palmitic acid compared with MUFA meal rich in oleic acid), Lithander et al. [50] observed a significant increase in PWV c-f (m/s) from baseline in the postprandial state; however, this effect was no longer significant when adjusted for the increase in MAP.Furthermore, FA composition (SFA-rich meal compared with MUFA-rich meal) had no influence on PWV c-f (m/s) (Table 5).
The only study measuring PWV (m/s) in subjects with increased CVD risk factors reported no influence of FA composition (control meal compared with EPA-rich meal compared with DHA-rich meal) on postprandial PWV c-f (m/s) [57] (Table 6).

Discussion
In this review, we aimed to summarize and analyze the existing evidence on the impact of dietary fat dose and FA composition on vascular function in metabolically healthy adults and individuals with increased CVD risk, measured by postprandial changes in FMD, PWV, and AIx.We specifically focused on studies that fed commercially available foods.

The impact of fat dose on vascular function
Studies showed that after an overnight fast of 10.0-12.5 h, a further extension of the fasting period did not affect FMD [45,46] or AIx [48].By contrast, consumption of an HFM (breakfast or lunch) resulted in a reduction in FMD [45,46] and AIx [48] from baseline.The energy and fat content of the HFMs were comparable between studies (Tables 2 and 4).
Six trials compared the impact of HFMs and LFMs on vascular function [40][41][42][43][44]47], providing inconsistent results (Tables 2-4).Bae et al. [40] and Benson et al. [42] reported that the HFM but not the LFM affected FMD in healthy adults, resulting in a significant group difference between meals.Both trials demonstrated strong methodical quality by feeding isoenergetic meals with a strongly varying fat content (53.4 g compared with 3 g; 1 g/kg BW compared with 0.04 g/kg BW).This observation agrees with Jackson et al. [64] who report that compared with meals containing <10 g fat, meals with a higher fat content (50-105 g) impair vascular reactivity.In a recent review, Zhao et al. [65] described 3 main mechanisms by which postprandial lipemia triggers endothelial dysfunction and atherosclerosis.First, postprandial increases in TGs and TG-rich lipoproteins result in direct damage to endothelial function; this is closely linked to an imbalance in vasodilator and vasoconstrictor factors.The vasodilator decrease mainly results from decreased NO and increased oxidative stress.The second factor impairing vascular function is increased oxidative stress and decreased antioxidant capacity induced by postprandial lipemia.During postprandial lipemia, the antioxidant enzymes glutathione peroxidase and superoxide dismutase decrease, whereas the excretion of oxidative stress markers 8-external prostaglandin F2 and free 8-iso-prostaglandin F 2α increases; production of reactive oxygen species is also intensified during the postprandial state.Third, consumption of an HFM induces transient, low-grade inflammation with impairment of the endothelial barrier.In this process, proinflammatory genes are upregulated in endothelial cells, leukocyte activation marker expression is increased, and the proinflammatory complement system is involved [65].Considering that, in the above-mentioned studies, the LFMs had no influence on FMD; these LFMs may not have contained enough fat (3 g, 0.04 g/kg BW) to trigger sufficient postprandial lipemia with subsequent endothelial dysfunction [40,42].This assumption is supported by the fact that in both studies, only consumption of the HFMs but not of the LFMs resulted in a significant increase in TGs compared with baseline values.
Consistent with the findings of Bae et al. [40] and Benson et al. [42], Esser et al. [43] also observed an effect of an HFM (95 g fat) on vascular function in healthy adults, which resulted in significantly lower postprandial FMD and AIx compared with baseline values (Table 2).One mechanism by which an HFM may induce a postprandial AIx reduction is a decrease in central systolic and diastolic blood pressure following meal intake, caused by transient relaxation of arterial smooth muscles in the general circulation [66].However, contrary to Bae et al. [40] and Benson et al. [42], Esser et al. [43] also reported a significant reduction in FMD and AIx from baseline subsequent to the LFM (14.5 g fat), without significant group differences between the HFM and LFM.The significant decrease in FMD 3 h after consumption of the LFM is surprising, especially given the results from Williams et al. [47], where a similar LFM (18.4 g fat) exerted no influence on FMD in healthy adults.
In addition to Williams et al. [47], 2 further studies detected no effect of either the HFM or the LFM on vascular function determined by FMD [41,44].There are several reasons to explain the lack of change in FMD subsequent to the consumption of an HFM.For example, certain factors, such as physical activity determine an individual's capacity to tolerate acute triggers that impair vascular function (e.g., an HFM) [67].Combined with small samples sizes (often only ~10 participants), low susceptibility to fat-induced modulation of vascular function might have prevented alterations in endothelial function following HFM consumption.Furthermore, short postprandial periods (e.g., 2 h), a small number of measurement time points (e.g., baseline and only 1 postprandial measurement), large time intervals between measurements (e.g., 4 h) may have meant that significant effects on vascular function were not detected in the postprandial period.Regarding the fact that an increase in TGs was observed during the postprandial period but no effect on vascular function was detected, Williams et al. [47] and Poitras et al. [44] noted that a rise in TGs may not consistently impair endothelial function.However, in 3 studies, the postprandial increase in TGs was correlated with the decrease in FMD assessed 2 h postprandially [40,41,46].Abbreviations: AIx, augmentation index; CHO, carbohydrate; CVD, cardiovascular disease; E%, energy percentage; FA, fatty acid; FMD, flow-mediated dilation; iAUC, incremental AUC; N/A, not available; PWV, pulse wave velocity; T2DM, type 2 diabetes mellitus. 1Age and BMI are given as mean AE SD or mean (95 % CI). 2 Data on energy intake in MJ or kJ were converted to kcal (1 kcal ¼ 4.184 kJ ¼ 0.004184 MJ). 3 Three additional test meals consisted of white bread (12 and 50 g available CHO) and pistachios; the nutrient composition and results of these meals are not stated here. 4SFA content was decreased and MUFA content was increased by a "high-oleic sunflower oil dairy-cow feeding strategy."The impact of FA composition on vascular function Most of the studies that investigated the impact of FA composition on AIx showed no differential effect of meal FA composition [49,50,56] (Tables 5 and 6).However, 2 studies showed a beneficial effect of a meal enriched with DHA [57] or EPA and DHA [55] on vascular function assessed by AIx.The favorable effect of marine n-3 PUFAs (EPA/DHA) on the endothelium is widely described, including a reduction of proatherogenic and prothrombotic factors (e.g., reduced expression of endothelial adhesion molecules and proinflammatory cytokines) [68,69].
The data on the impact of FA composition on FMD is highly inconsistent (Tables 5-7).Six studies reported no postprandial change in FMD after consumption of meals with varying FA compositions in healthy adults [53,54,63] or adults with CVD risk factors [58,59,61].However, Rudolph et al. [52] reported that several burger meals resulted in a decrease in FMD compared with baseline, but without significant group differences.Nicholls et al. [51] found no significant group differences in FMD change from baseline after consumption of meals with 2 different fat sources; in this study, only the SFA-rich meal (coconut oil) and not the PUFA-rich meal (safflower oil) led to a significant reduction in FMD from baseline.Mechanistic studies suggest differential effects of FAs on vascular function at the molecular level.Although in human aortic endothelial cells, incubation with oleic acid promoted signal transduction via the PI3K/Akt/endothelial nitric oxide synthase (eNOS) pathway [70], palmitic acid inhibited the Akt/eNOS pathway in human umbilical vein endothelial cells, leading to a decrease in NO production by inhibition of eNOS activity [71].On the level of FA classes, incubation of human aortic endothelial cells with SFAs and n-3 PUFAs resulted in greater downregulation of the PI3K/Akt pathway than with SFAs alone [70].The assumption that the dietary FA composition acts as a modulator of vascular function is supported by 4 of the included studies, all of which reported a differential effect of meal FA composition on postprandial FMD [49,60,62,63].Berry et al. [49] observed that in healthy adults, a MUFA-rich meal (high-oleic sunflower oil) led to a significantly greater postprandial reduction in FMD than the SFA-rich meal (shea butter blend).Meanwhile, Cutruzzol a et al. [63] reported that in T1DM subjects, the SFA-rich meal (butter) resulted in a significantly lower FMD than the MUFA-rich meal (olive oil).Cort es et al. [62] also fed a MUFA-rich meal enriched with olive oil, but compared the effects on FMD with those of a walnut-rich meal, reporting a decrease in FMD from baseline after an olive oil-rich meal in both healthy and hypercholesterolemic adults.Furthermore, FMD in healthy adults remained unchanged from baseline after the walnut meal, whereas FMD increased in hypercholesterolemic subjects.By showing an increase in FMD from baseline when enriching a MUFA-rich meal with ALA or EPA and DHA, West et al. [60] provided evidence for a favorable effect of n-3 PUFAs on vascular function in T2DM subjects with high fasting TGs.

The role of health status
One study that focused on the impact of fat dose on vascular function included healthy, lean adults and adults with obesity or T2DM (Table 4) [48].Lean subjects and those with T2DM had a higher AIx incremental AUC after consuming an HFM than obese participants.In addition, T2DM subjects showed a delay in time to return to baseline AIx values than lean individuals.Besides, in 2 different trials, Bae et al. [40,41] used the same HFM and LFM in healthy adults and CAD patients.Although in healthy adults, consumption of the HFM resulted in a significantly lower FMD than the LFM, no effect was observed in CAD subjects (Tables 2  and 3).
Concerning FA composition, 2 studies included healthy subjects and adults with hypercholesterolemia [62] and T1DM [63] (Table 7).Cort es et al. [62] reported that only in hypercholesterolemic patients but not in healthy adults, a walnut meal led to an increase in FMD.Likewise, in the study of Cutruzzol a et al. [63], FMD was unaffected by meals enriched with butter or olive oil in healthy adults, whereas in subjects with T1DM, FMD postprandially increased following the olive oil meal compared with the butter meal.In addition, West et al. [60] investigated patients with T2DM, with and without high fasting TGs.Only in subjects with high fasting TGs did enrichment of a MUFA-containing meal with ALA or EPA and DHA result in a postprandial increase in FMD (Table 6).

Strengths and limitations
To our knowledge, this is the first review to systematically investigate the effects of fat dose and FA composition on various subclinical markers of atherosclerosis in healthy adults and CVD risk patients.The inclusion of 3 diagnostic parameters of vascular function (FMD, PWV, and AIx) enabled us to evaluate both vascular reactivity and arterial stiffness.In addition, we increased the practical application of our findings by using a food-based approach, focusing on fat sources and their FA composition from whole foods.Nevertheless, because of our focus on fat dose and FA composition, a possible influence of other meal characteristics (e.g., content of energy, carbohydrates, and antioxidants) on vascular function that might contribute to the heterogeneity of study results was not considered.The high heterogeneity of the study results was certainly also influenced by the broad range of fat amount administered via the LFMs (0-18.4g) and HFMs (29-95 g).Because of the high variation of meal compositions (e.g., energy content and fat source), study protocols (e.g., time points of measurements and time period of protocols), and study populations and comparisons, we did not perform a meta-analysis.To obtain convincing results and more consistent evidence on the effects of meal composition on vascular function, standardization of postprandial protocols is required (Table 8).To provide a more comprehensive view of the influence of meal composition on vascular function, in addition to the diagnostic parameters presented in this review, other target systems such as inflammatory processes associated with the postprandial state and postprandial endothelial activation should be investigated.Because vascular function is multifactorially determined, and atherosclerotic processes are too complex to be reduced to just a few mechanisms (e.g., atherosclerosis caused by HFM intake), in addition to analyzing the acute influence of meal intake, other elements (e.g., habitual diet and psychologic influences) should be considered in the research on precipitating and protective factors on endothelial dysfunction and atherosclerosis.

Conclusions
This review revealed 3 main findings.First, evidence suggests that meal consumption results in decreases in FMD and AIx; specifically, higher fat doses appear to impair vascular reactivity measured by FMD more strongly than lower fat doses.Second, concerning FA composition, most studies indicate no clinically relevant or contradictory effects on subclinical atherosclerosis markers (FMD, PWV, and AIx).One exception might be marine n-3 PUFAs (EPA and DHA), as data from 3 studies suggest a beneficial effect on acute vascular function.Third, some studies found differences in the vascular response to meals with varying fat doses or FA composition between metabolically healthy subjects and subjects with CVD risk factors, but based on the analyzed literature with highly heterogenic populations, the specific effects could not be deduced.Our current findings of the impact of meal total fat content and FA composition on postprandial vascular function assessed by FMD, PWV, and AIx are based on meal studies in which a variety of fat sources (e.g., virgin or refined vegetable oils, milk fat, and butter) was used in different amounts and meal recipes.At this time, it cannot be concluded which fat source in which amount and meal composition has beneficial effects on postprandial vascular function.

Further directions
To enhance the meaningfulness of systematic reviews and to allow valid meta-analyses concerning the effects of meal composition on vascular function, we strongly recommend standardization of postprandial protocols.In Table 8, we provide an overview of fundamental aspects concerning study design.The recommendations mainly refer to the test meal and postprandial period.Meals should be fed as breakfast after an overnight fast (!10 h).To enhance practical applications, and possibly derive subsequent dietary recommendations, the use of commercially available foods is advisable.With respect to the assumed connection between postprandial lipemia and alterations in vascular function, we recommend a fat amount of !50 g/meal to induce reliable lipemia.To allow synthesis and comparison of data from different studies, nutrient and FA profiles should be characterized.Finally, noninvasive measurement of vascular function should be performed after a resting period in a supine position by trained personnel.

TABLE 1
Inclusion and exclusion criteria 1.

Electronic search in PubMed (n = 116) Relevant abstract (n = 40) 77 publications excluded based on abstract Inclusion in review (n = 24) 16 publications excluded based on full text 2. Electronic search in additional databases 114 publications excluded based on abstract
FIGURE 1. Flowchart of the article search and selection process.FA, fatty acid; HFM, high-fat meal.H.F.Kien es, S. Egert Current Developments in Nutrition 7 (2023) 102025

TABLE 2
Postprandial studies investigating the effects of fat dose on vascular function in healthy adults1

TABLE 3
Postprandial studies investigating the effects of fat dose on vascular function in adults with CVD risk factors 1 flow-mediated dilation; HFM, high-fat meal; LFM, low-fat meal; N/A, not available.Two additional groups received angiotensin-converting enzyme inhibition and fibrates in addition to HFM; methods and results are not stated here.

TABLE 4
Postprandial studies investigating the effects of fat dose on vascular function in healthy adults and adults with CVD risk factors1 Abbreviations: AIx, augmentation index; CHO, carbohydrate; FA, fatty acid; HFM, high-fat meal; iAUC, incremental AUC; N/A, not available; T2DM, type 2 diabetes mellitus.1AgeandBMIare given as mean AE SD or median (interquartile range).2Dataon energy intake in MJ or kJ were converted to kcal (1 kcal ¼ 4.184 kJ ¼ 0.004184 MJ).H.F. Kien es, S. Egert Current Developments in Nutrition 7 (2023) 102025

TABLE 5
Postprandial studies investigating the effects of FA composition on vascular function in healthy adults1

TABLE 5 (
Abbreviations: AIx, augmentation index; BW, body weight; CHO, carbohydrate; E%, energy percentage; FA, fatty acid; FMD, flow-mediated dilation; LC, long chain; MPA; N/A, not available; PWV, pulse wave velocity.1 Age and BMI are given as mean AE SD. 2 Data on energy intake in MJ or kJ were converted to kcal (1 kcal ¼ 4.184 kJ ¼ 0.004184 MJ). 3 Test meals were consumed 5 h after a low-fat, standard breakfast (400 kcal, 2.1 g of fat).4Inaddition to healthy adults, HIV-infected adults with and without antiretroviral therapy were studied; methods and results are not stated here.H.F. Kien es, S. Egert Current Developments in Nutrition 7 (2023) 102025

TABLE 6
Postprandial studies investigating the effects of FA composition on vascular function in adults with CVD risk factors1

TABLE 7
Postprandial studies investigating the effects of FA composition on vascular function in healthy adults and adults with CVD risk factors1 Abbreviations: CHO, carbohydrate; CVD, cardiovascular disease; FA, fatty acid; FMD, flow-mediated dilation; T1DM, type 1 diabetes mellitus.1Ageand BMI are given as mean AE SD.

TABLE 8
Recommendations for the design of future postprandial studies on vascular function .F. Kien es, S. Egert Current Developments in Nutrition 7 (2023) 102025 H